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1.  How to improve influenza vaccine coverage of healthcare personnel 
Influenza causes substantial morbidity and mortality worldwide each year. Healthcare-associated influenza is a frequent event. Health care personnel (HCP) may be the source for infecting patients and may propagate nosocomial outbreaks. All HCP should receive a dose of influenza vaccine each year to protect themselves and others. This commentary will discuss the study recently published in the IJHPR by Nutman and Yoeli which assessed the beliefs and attitudes of HCP in an Israel hospital regarding influenza and the influenza vaccine. Unfortunately, as noted by Nutman and Yoeli in this issue many HCP in Israel choose not to receive influenza immunization and many harbor misconceptions regarding their risk for influenza as well as the benefits of influenza vaccine. We also discuss proven methods to increase acceptance by HCP for receiving an annual influenza vaccine.
doi:10.1186/s13584-016-0122-3
PMCID: PMC5162081  PMID: 28018575
Occupational health; Healthcare personnel; Vaccines; Influenza
2.  Short Operative Duration and Surgical Site Infection Risk in Hip and Knee Arthroplasty Procedures 
OBJECTIVE
To determine the association (1) between shorter operative duration and surgical site infection (SSI) and (2) between surgeon median operative duration and SSI risk among first-time hip and knee arthroplasties.
DESIGN
Retrospective cohort study
SETTING
A total of 43 community hospitals located in the southeastern United States.
PATIENTS
Adults who developed SSIs according to National Healthcare Safety Network criteria within 365 days of first-time knee or hip arthroplasties performed between January 1, 2008 and December 31, 2012.
METHODS
Log-binomial regression models estimated the association (1) between operative duration and SSI outcome and (2) between surgeon median operative duration and SSI outcome. Hip and knee arthroplasties were evaluated in separate models. Each model was adjusted for American Society of Anesthesiology score and patient age.
RESULTS
A total of 25,531 hip arthroplasties and 42,187 knee arthroplasties were included in the study. The risk of SSI in knee arthroplasties with an operative duration shorter than the 25th percentile was 0.40 times the risk of SSI in knee arthroplasties with an operative duration between the 25th and 75th percentile (risk ratio [RR], 0.40; 95% confidence interval [CI], 0.38–0.56; P <.01). Short operative duration did not demonstrate significant association with SSI for hip arthroplasties (RR, 1.04; 95% CI, 0.79–1.37; P =.36). Knee arthroplasty surgeons with shorter median operative durations had a lower risk of SSI than surgeons with typical median operative durations (RR, 0.52; 95% CI, 0.43–0.64; P <.01).
CONCLUSIONS
Short operative durations were not associated with a higher SSI risk for knee or hip arthroplasty procedures in our analysis.
doi:10.1017/ice.2015.222
PMCID: PMC4748707  PMID: 26391277
3.  Personal Protective Equipment - Protecting Healthcare Providers in an Ebola Outbreak 
Clinical therapeutics  2015;37(11):2402-2410.
Purpose
The current Ebola epidemic that has devastated West Africa has infected and killed more healthcare providers than any other outbreak in the history of this virus. An improved understanding of pathogen transmission and the institution of strategies to protect infection healthcare providers are needed in infectious disease outbreak. This review connects what is known about Ebola virus transmission with personal protective equipment designed to arrest nosocomial transmission.
Methods
Articles pertaining to filovirus transmission and personal protective equipment in filovirus outbreaks were reviewed and are presented. Additionally, studies evaluating PPE as well as donning and doffing strategies are also presented.
Findings
Personal Protective equipment is one step in a comprehensive infection prevention and control strategy that is required to protect healthcare providers. Given that the Ebola virus is primarily transmitted through direct contact of mucous membranes and cuts in the skin with infected patients and/or their bodily fluids, it is necessary to cover these potential portals of infection with PPE as part of a structured and instructed donning and doffing procedure.
Implications
Current recommendations about PPE and the donning and doffing processes are based on anecdotal experience. However the use of non-human viruses can help provide evidence based guidelines on both PPE and processes.
doi:10.1016/j.clinthera.2015.07.007
PMCID: PMC4661082  PMID: 26452427
Ebola; Personal Protective Equipment; Transmission; Infection Prevention and Control; Outbreak
4.  Impact of a Routine, Opt-Out HIV Testing Program on HIV Testing and Case Detection in North Carolina Sexually-Transmitted Disease Clinics 
Sexually transmitted diseases  2014;41(6):395-402.
The impact of routine, opt-out HIV testing programs in clinical settings is inconclusive. The objective of this study was to estimate the impact of an expanded, routine HIV testing program in North Carolina sexually transmitted disease (STD) clinics on HIV testing and case detection.
Adults aged 18–64 who received an HIV test in a North Carolina STD clinic July 1, 2005 through June 30, 2011 were included in this analysis, dichotomized at the date of implementation on November 1, 2007. HIV testing and case detection counts and rates were analyzed using interrupted time series analysis, and Poisson and multilevel logistic regression.
Pre-intervention, 426 new HIV-infected cases were identified from 128,029 tests (0.33%), whereas 816 new HIV-infected cases were found from 274,745 tests post-intervention (0.30%). Pre-intervention, HIV testing increased by 55 tests per month (95% confidence interval [CI]: 41, 72), but only 34 tests per month (95% CI: 26, 42) post-intervention. Increases in HIV testing rates were most pronounced in females and non-Hispanic whites. A slight pre-intervention decline in case detection was mitigated by the intervention (mean difference [MD]=0.01; 95% CI: −0.02, 0.05). Increases in case detection rates were observed among females and non-Hispanic blacks.
The impact of a routine HIV screening in North Carolina STD clinics was marginal, with the greatest benefit among persons not traditionally targeted for HIV testing. The use of a pre-intervention comparison period identified important temporal trends that otherwise would have been ignored.
doi:10.1097/OLQ.0000000000000141
PMCID: PMC5056640  PMID: 24825338
routine HIV testing; STD clinic; intervention analysis
5.  Development of Novel Methods to Define Deficits in Appendicular Lean Mass Relative to Fat Mass 
PLoS ONE  2016;11(10):e0164385.
Background
Recent studies suggest that adjustment of measures of lean mass for adiposity improves associations with physical function. Our objective was to develop and test a method to adjust appendicular lean mass for adiposity.
Methods
Whole-body DXA data in 14,850 adults in the National Health and Nutrition Examination Survey were used to generate sex-, and race-specific standard deviation scores (Z-Scores relative to age and T-scores relative to 25 year-olds) for appendicular lean mass index (ALMI, kg/m2) and fat mass index (FMI, kg/m2). Correlations between ALMI and FMI Z- and T-Scores were assessed within demographic categories. Fat-adjusted ALMI (ALMIFMI) scores were determined using residual methods. Sarcopenia was defined as a T-Score <-2.0 and low lean for age as a Z-Score <-1.0. Correlations with physical function were assessed in an at-risk population.
Results
Positive associations between ALMI and FMI Z- and T-Scores were significant (R >0.50; p<0.001) within all demographic categories. The impact of a unit greater FMI Z-score on ALMI Z-score was less in the elderly, men, white subjects, and among individuals with lower FMI (all tests for interaction p<0.001). There was fair agreement between ALMI and ALMIFMI estimates of sarcopenia and low lean for age [Kappa: 0.46, 0.52, respectively (p<0.0001)]. Elderly subjects were likely to be re-classified as sarcopenic while young subjects were likely to be re-classified as normal using ALMIFMI. ALMIFMI T-scores resulted in approximately twice the number of subjects defined as sarcopenic, compared with ALMI T-Scores. (1299 v. 534). Among rheumatoid arthritis patients, ALMIFMI Z-scores correlated with physical function (Health Assessment Questionnaire: rho = -0.22, p = 0.04; Short Physical Performance Battery: rho = 0.27, p = 0.01); however, the ALMI Z-Score did not.
Conclusions
Adjustment of ALMI for the confounding association with FMI impacts the definition of lean mass deficits. These methods provide a practical tool for investigators and clinicians based on population-based reference data.
doi:10.1371/journal.pone.0164385
PMCID: PMC5056731  PMID: 27723820
6.  Type 1 Diabetes Is Associated With an Increased Risk of Fracture Across the Life Span: A Population-Based Cohort Study Using The Health Improvement Network (THIN) 
Diabetes Care  2015;38(10):1913-1920.
OBJECTIVE
This study was conducted to determine if type 1 diabetes is associated with an increased risk of fracture across the life span.
RESEARCH DESIGN AND METHODS
This population-based cohort study used data from The Health Improvement Network (THIN) in the U.K. (data from 1994 to 2012), in which 30,394 participants aged 0–89 years with type 1 diabetes were compared with 303,872 randomly selected age-, sex-, and practice-matched participants without diabetes. Cox regression analysis was used to determine hazard ratios (HRs) for incident fracture in participants with type 1 diabetes.
RESULTS
A total of 334,266 participants, median age 34 years, were monitored for 1.9 million person-years. HR were lowest in males and females age <20 years, with HR 1.14 (95% CI 1.01–1.29) and 1.35 (95% CI 1.12–1.63), respectively. Risk was highest in men 60–69 years (HR 2.18 [95% CI 1.79–2.65]), and in women 40–49 years (HR 2.03 [95% CI 1.73–2.39]). Lower extremity fractures comprised a higher proportion of incident fractures in participants with versus those without type 1 diabetes (31.1% vs. 25.1% in males, 39.3% vs. 32% in females; P < 0.001). Secondary analyses for incident hip fractures identified the highest HR of 5.64 (95% CI 3.55–8.97) in men 60–69 years and the highest HR of 5.63 (95% CI 2.25–14.11) in women 30–39 years.
CONCLUSIONS
Type 1 diabetes was associated with increased risk of incident fracture that began in childhood and extended across the life span. Participants with type 1 diabetes sustained a disproportionately greater number of lower extremity fractures. These findings have important public health implications, given the increasing prevalence of type 1 diabetes and the morbidity and mortality associated with hip fractures.
doi:10.2337/dc15-0783
PMCID: PMC4580610  PMID: 26216874
9.  Next-Generation Sequencing and Comparative Analysis of Sequential Outbreaks Caused by Multidrug-Resistant Acinetobacter baumannii at a Large Academic Burn Center 
Next-generation sequencing (NGS) analysis has emerged as a promising molecular epidemiological method for investigating health care-associated outbreaks. Here, we used NGS to investigate a 3-year outbreak of multidrug-resistant Acinetobacter baumannii (MDRAB) at a large academic burn center. A reference genome from the index case was generated using de novo assembly of PacBio reads. Forty-six MDRAB isolates were analyzed by pulsed-field gel electrophoresis (PFGE) and sequenced using an Illumina platform. After mapping to the index case reference genome, four samples were excluded due to low coverage, leaving 42 samples for further analysis. Multilocus sequence types (MLST) and the presence of acquired resistance genes were also determined from the sequencing data. A transmission network was inferred from genomic and epidemiological data using a Bayesian framework. Based on single-nucleotide variant (SNV) differences, this MDRAB outbreak represented three sequential outbreaks caused by distinct clones. The first and second outbreaks were caused by sequence type 2 (ST2), while the third outbreak was caused by ST79. For the second outbreak, the MLST and PFGE results were discordant. However, NGS-based SNV typing detected a recombination event and consequently enabled a more accurate phylogenetic analysis. The distribution of resistance genes varied among the three outbreaks. The first- and second-outbreak strains possessed a blaOXA-23-like group, while the third-outbreak strains harbored a blaOXA-40-like group. NGS-based analysis demonstrated the superior resolution of outbreak transmission networks for MDRAB and provided insight into the mechanisms of strain diversification between sequential outbreaks through recombination.
doi:10.1128/AAC.02014-15
PMCID: PMC4775949  PMID: 26643351
10.  Resolving Uncertainty About the Intolerance of Uncertainty Scale–12: Application of Modern Psychometric Strategies 
Journal of personality assessment  2015;98(2):200-208.
In this study, we evaluated the factor structure, reliability estimates, item parameters, and differential correlates of the short form of the Intolerance of Uncertainty Scale (Carleton, Norton, & Asmundson, 2007) in samples of undergraduate women (n = 387) and men (n = 276) ranging in age from 18 to 49 years (M = 20.20, SD = 3.91). This instrument was designed to measure 2 facets of intolerance of uncertainty— prospective anxiety and inhibitory anxiety—although total scores on the measure are often used. A major objective of this study was to determine the degree to which derivation of total versus subscale scores is empirically permissible. Comparison of a bifactor model to a unidimensional model and a 2-factor correlated traits model indicated that the bifactor model exhibited superior fit to the sample data. This model provided evidence of a strong general intolerance of uncertainty factor that was more reliable and accounted for significantly more common variance than either subscale factor. Examination of the item response theory slope parameters revealed negligible bias in the measure’s items across genders. Finally, a series of simultaneous regression analyses was conducted to examine differential correlates of the measure’s total scale scores for men and women.
doi:10.1080/00223891.2015.1070355
PMCID: PMC4809643  PMID: 26542301
11.  Reduction of Healthcare-Associated Infections by Exceeding High Compliance with Hand Hygiene Practices 
Emerging Infectious Diseases  2016;22(9):1628-1630.
Improving hand hygiene from high to very high compliance has not been documented to decrease healthcare-associated infections. We conducted longitudinal analyses during 2013–2015 in an 853-bed hospital and observed a significantly increased hand hygiene compliance rate (p<0.001) and a significantly decreased healthcare-associated infection rate (p = 0.0066).
doi:10.3201/eid2209.151440
PMCID: PMC4994356  PMID: 27532259
hand hygiene; healthcare-associated infections; bacteria; enteric infections; nosocomial infections; compliance; Clostridium difficile
12.  Is Aerosalization a Problem With Carbapenem-Resistant Acinetobacter baumannii in Thailand Hospital? 
Open Forum Infectious Diseases  2016;3(3):ofw124.
We evaluated the presence of air contamination with carbapenem-resistant Acinetobacter baumannii (CRAB) in medical units where patients with CRAB pneumonia were hospitalized, and in Obstetrics and Gynecology units with open-air ventilation in-patient settings. There was no evidence of CRAB contamination in either of the units.
doi:10.1093/ofid/ofw124
PMCID: PMC4942757  PMID: 27419187
Acinetobacter baumannii; aerosolization; carbapenem-resistant; Thailand; ventilator-associated pneumonia
13.  S100A1 Binds to the Calmodulin-binding Site of Ryanodine Receptor and Modulates Skeletal Muscle Excitation-Contraction Coupling*S 
The Journal of biological chemistry  2007;283(8):5046-5057.
S100A1, a 21-kDa dimeric Ca2+-binding protein, is an enhancer of cardiac Ca2+ release and contractility and a potential therapeutic agent for the treatment of cardiomyopathy. The role of S100A1 in skeletal muscle has been less well defined. Additionally, the precise molecular mechanism underlying S100A1 modulation of sarcoplasmic reticulum Ca2+ release in striated muscle has not been fully elucidated. Here, utilizing a genetic approach to knock out S100A1, we demonstrate a direct physiological role of S100A1 in excitation-contraction coupling in skeletal muscle. We show that the absence of S100A1 leads to decreased global myoplasmic Ca2+ transients following electrical excitation. Using high speed confocal microscopy, we demonstrate with high temporal resolution depressed activation of sarcoplasmic reticulum Ca2+ release in S100A1−/− muscle fibers. Through competition assays with sarcoplasmic reticulum vesicles and through tryptophan fluorescence experiments, we also identify a novel S100A1-binding site on the cytoplasmic face of the intact ryanodine receptor that is conserved throughout striated muscle and corresponds to a previously identified calmodulin-binding site. Using a 12-mer peptide of this putative binding domain, we demonstrate low micromolar binding affinity to S100A1. NMR spectroscopy reveals this peptide binds within the Ca2+-dependent hydrophobic pocket of S100A1. Taken together, these data suggest that S100A1 plays a significant role in skeletal muscle excitation-contraction coupling, primarily through specific interactions with a conserved binding domain of the ryanodine receptor. This warrants further investigation into the use of S100A1 as a therapeutic target for the treatment of both cardiac and skeletal myopathies.
doi:10.1074/jbc.M709231200
PMCID: PMC4821168  PMID: 18089560
14.  Exome sequencing reveals a nonsense mutation in MMP13 as a new cause of autosomal recessive metaphyseal anadysplasia 
Metaphyseal anadysplasia (MANDP) is an uncommon chondrodysplasia characterized by early-onset metaphyseal dysplasia and short stature that improves with age. MANDP is caused by mutations in the matrix metalloproteinase (MMP) 9 and 13 genes. Autosomal dominant (AD) MANDP has been described as more severe, and has been associated with dominant-negative MMP13 mutations that suppress activity of both MMP9 and MMP13; autosomal recessive (AR) MANDP has been described as a milder form associated with AR missense mutations in MMP9 or MMP13. Here we describe the molecular characterization of skeletal dysplasia in two brothers who presented with short stature and mixed epiphyseal and metaphyseal dysplasia. Whole-exome sequencing (WES) identified a homozygous C>T transition mutation in exon 2 of MMP13 (c.325C>T) on chromosome 11q22.2 resulting in a premature stop codon p.(R109*) that is predicted to abolish MMP13 activity. This report extends the MANDP phenotype by illustrating that AR nonsense mutations in MMP13 can lead to short stature that persists beyond childhood.
doi:10.1038/ejhg.2014.76
PMCID: PMC4297904  PMID: 24781753
15.  Small Molecule Inhibitors of Ca2+-S100B Reveal Two Protein Conformations 
Journal of medicinal chemistry  2016;59(2):592-608.
The drug pentamidine inhibits calcium-dependent complex formation with p53 (CaS100B•p53) in malignant melanoma (MM), and restores p53 tumor suppressor activity in vivo. However, off-target effects associated with this drug were problematic in MM patients. Structure-activity relationship (SAR) studies were therefore completed here with 23 pentamidine analogues, and X-ray structures of CaS100B•inhibitor complexes revealed that the C-terminus of S100B adopts two different conformations, with location of Phe-87 and Phe-88 being the distinguishing feature and termed the “FF-Gate”. For symmetric pentamidine analogues (CaS100B•5a, CaS100B•6b) a channel between Sites 1 and 2 on S100B was occluded by residue Phe-88, but for an asymmetric pentamidine analogue (CaS100B•17), this same channel was open. The CaS100B•17 structure illustrates, for the first time, a pentamidine analog capable of binding the “open” form of the “FF-gate” and provides a means to block all three “hot spots” on CaS100B, which will impact next generation CaS100B•p53 inhibitor design.
doi:10.1021/acs.jmedchem.5b01369
PMCID: PMC4732916  PMID: 26727270
16.  Etiology of Childhood Diarrhea Following Rotavirus Vaccine Introduction: A Prospective, Population-Based Study in Nicaragua 
Background
Nicaragua was the first developing nation to implement routine immunization with the pentavalent rotavirus vaccine (RV5). In this RV5-immunized population, understanding infectious etiologies of childhood diarrhea is necessary to direct diarrhea treatment and prevention efforts.
Methods
We followed a population-based sample of children less than 5 years in León, Nicaragua for diarrhea episodes through household visits. Information was obtained on RV5 history and sociodemographics. Stool samples collected during diarrhea episodes and among healthy children underwent laboratory analysis for viral, bacterial, and parasitic enteropathogens. Detection frequency and incidence of each enteropathogen was calculated.
Results
The 826 children in the cohort experienced 677 diarrhea episodes during 607.5 child-years of exposure time (1.1 episodes per child-year). At least one enteropathogen was detected among 61.1% of the 337 diarrheal stools collected. The most common enteropathogens among diarrheal stools were: norovirus (20.4%), sapovirus (16.6%), enteropathogenic Escherichia coli (EPEC, 11.3%), Entamoeba histolytica/dispar (8.3%), Giardia lamblia (8.0%), and enterotoxigenic E.coli (ETEC, 7.7%), with rotavirus detected among 5.3% of diarrheal stools. EPEC and ETEC were frequently detected among stools from healthy children. Among children with diarrhea, norovirus was more commonly detected among younger children (< 2 years) and G. lamblia was more commonly detected among older children (2-4 years). The mean age of rotavirus detection was 34.6 months.
Conclusions
In this Central American community following RV5 introduction, rotavirus was not commonly detected among children with diarrhea. Prevention and appropriate management of norovirus and sapovirus should be considered to further reduce the burden of diarrheal disease.
doi:10.1097/INF.0000000000000427
PMCID: PMC4216626  PMID: 24879131
Childhood; Community; Diarrhea; Nicaragua; Rotavirus vaccine
17.  Impact of a Rapid Microarray-Based Assay for Identification of Positive Blood Cultures for Treatment Optimization for Patients with Streptococcal and Enterococcal Bacteremia 
Journal of Clinical Microbiology  2015;53(4):1411-1414.
Implementation of the Verigene Gram-positive blood culture test led to reductions in time to acceptable antibiotic overall (1.9 versus 13.2 h, respectively; P = 0.04) and time to appropriate antibiotic for patients with vancomycin-resistant Enterococcus (4.2 versus 43.7 h; P = 0.006) and viridans group Streptococcus (0.2 versus 7.1 h; P = 0.02).
doi:10.1128/JCM.00104-15
PMCID: PMC4365208  PMID: 25673785
18.  Covalent Small Molecule Inhibitors of Ca2+-Bound S100B 
Biochemistry  2014;53(42):6628-6640.
Elevated levels of the tumor marker S100B are observed in malignant melanoma, and this EF-hand-containing protein was shown to directly bind wild-type (wt) p53 in a Ca2+-dependent manner, dissociate the p53 tetramer, and inhibit its tumor suppression functions. Likewise, inhibiting S100B with small interfering RNA (siRNAS100B) is sufficient to restore wild-type p53 levels and its downstream gene products and induce the arrest of cell growth and UV-dependent apoptosis in malignant melanoma. Therefore, it is a goal to develop S100B inhibitors (SBiXs) that inhibit the S100B–p53 complex and restore active p53 in this deadly cancer. Using a structure–activity relationship by nuclear magnetic resonance approach (SAR by NMR), three persistent binding pockets are found on S100B, termed sites 1–3. While inhibitors that simultaneously bind sites 2 and 3 are in place, no molecules that simultaneously bind all three persistent sites are available. For this purpose, Cys84 was used in this study as a potential means to bridge sites 1 and 2 because it is located in a small crevice between these two deeper pockets on the protein. Using a fluorescence polarization competition assay, several Cys84-modified S100B complexes were identified and examined further. For five such SBiX–S100B complexes, crystallographic structures confirmed their covalent binding to Cys84 near site 2 and thus present straightforward chemical biology strategies for bridging sites 1 and 3. Importantly, one such compound, SC1982, showed an S100B-dependent death response in assays with WM115 malignant melanoma cells, so it will be particularly useful for the design of SBiX molecules with improved affinity and specificity.
doi:10.1021/bi5005552
PMCID: PMC4211652  PMID: 25268459
19.  A piRNA-like small RNA interacts with and modulates p-ERM proteins in human somatic cells 
Nature Communications  2015;6:7316.
PIWI-interacting RNAs (piRNAs) are thought to silence transposon and gene expression during development. However, the roles of piRNAs in somatic tissues are largely unknown. Here we report the identification of 555 piRNAs in human lung bronchial epithelial (HBE) and non-small cell lung cancer (NSCLC) cell lines, including 295 that do not exist in databases termed as piRNA-like sncRNAs or piRNA-Ls. Distinctive piRNA/piRNA-L expression patterns are observed between HBE and NSCLC cells. piRNA-like-163 (piR-L-163), the top downregulated piRNA-L in NSCLC cells, binds directly to phosphorylated ERM proteins (p-ERM), which is dependent on the central part of UUNNUUUNNUU motif in piR-L-163 and the RRRKPDT element in ERM. The piR-L-163/p-ERM interaction is critical for p-ERM's binding capability to filamentous actin (F-actin) and ERM-binding phosphoprotein 50 (EBP50). Thus, piRNA/piRNA-L may play a regulatory role through direct interaction with proteins in physiological and pathophysiological conditions.
PIWI-interacting RNAs (piRNAs) suppress transposon and gene expression during development. Here, the authors identify many piRNAs and piRNA-like small RNAs in 11 human cell lines, and show that one piRNA-like small RNA binds to phosphorylated ERM proteins to regulate cancer cell migration and invasion.
doi:10.1038/ncomms8316
PMCID: PMC4557300  PMID: 26095918
20.  Continuous subcutaneous IGF-1 therapy via insulin pump in a patient with Donohue syndrome 
Donohue syndrome (DS) is a severe form of congenital insulin resistance due to mutation(s) in the insulin receptor (INSR) gene. Given the similarities between insulin and insulin-like growth factor 1 (IGF-1) receptors, recombinant human IGF-1 (rhIGF-1) has been used to treat severe insulin resistance due to INSR mutation(s). Traditional subcutaneous therapy may be limited by the shortened IGF-1 half-life in these patients. We report the case of a female with molecularly confirmed DS treated with continuous rhIGF-1 therapy via an insulin pump. With treatment, the patient’s hemoglobin A1c decreased from 9.8% to 8.8%, and her weight increased by 0.8 kg. Development of an ovarian tumor complicated her course, but it was unclear whether this was related to rhIGF-1 therapy. Limited treatment options exist for patients with DS. The use of continuous rhIGF-1 via an insulin pump may be a viable option, although further experience is needed to establish safety and efficacy.
doi:10.1515/jpem-2013-0402
PMCID: PMC4535795  PMID: 25153212
Donohue syndrome; insulin-like growth factor; insulin infusion systems; insulin resistance
21.  Assessment of Time to Clinical Response, a Proxy for Discharge Readiness, among Hospitalized Patients with Community-Acquired Pneumonia Who Received either Ceftaroline Fosamil or Ceftriaxone in Two Phase III FOCUS Trials 
The primary driver of health care costs for patients with community-acquired pneumonia (CAP) is the hospital length of stay (LOS). Unfortunately, hospital LOS comparisons are difficult to make from phase III CAP trials because of their structured designs and prespecified treatment durations. However, an opportunity still exists to draw inferences about potential LOS differences between treatments through the use of surrogates for hospital discharge. The intent of this study was to quantify the time to a clinical response, a proxy for the time to discharge readiness, among hospitalized CAP patients who received either ceftaroline or ceftriaxone in two phase III CAP FOCUS clinical trials. On the basis of the Infectious Diseases Society of America and American Thoracic Society CAP management guidelines and recent FDA guidance documents for community-acquired bacterial pneumonia, a post hoc adjudication algorithm was constructed a priori to compare the time to a clinical response, a proxy for the time to discharge readiness, between patients who received ceftaroline or ceftriaxone. Overall, 1,116 patients (ceftaroline, n = 562; ceftriaxone, n = 554) from the pooled FOCUS trials met the selection criteria for this analysis. Kaplan-Meier analyses showed that ceftaroline was associated with a shorter time, measured in days, to meeting the clinical response criteria (P = 0.03). Of the patients on ceftaroline, 61.0, 76.1, and 83.6% achieved a clinical response by days 3, 4, and 5, compared to 54.3, 69.8, and 79.3% of the ceftriaxone-treated patients. In the Cox regression, ceftaroline was associated with a shorter time to a clinical response (HR, 1.16, P = 0.02). The methodology employed here provides a framework to draw comparative effectiveness inferences from phase III CAP efficacy trials. (The FOCUS trials whose data were analyzed in this study have been registered at ClinicalTrials.gov under registration no. NCT00621504 and NCT00509106.)
doi:10.1128/AAC.03643-14
PMCID: PMC4335888  PMID: 25487791
23.  A Comparison of Environmental Contamination by Patients Infected or Colonized with Methicillin-Resistant Staphylococcus aureus or Vancomycin-Resistant Enterococci: A Multicenter Study 
A total of 1,023 environmental surfaces were sampled from 45 rooms with patients infected or colonized with methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococci (VRE) before terminal room cleaning. Colonized patients had higher median total target colony-forming units (CFU) of MRSA or VRE than did infected patients (median, 25 CFU [interquartile range, 0–106 CFU] vs 0 CFU [interquartile range, 0–29 CFU]; P = .033).
doi:10.1086/676861
PMCID: PMC4219411  PMID: 24915217
24.  Hospital-Acquired Clostridium difficile Infections Estimating All-Cause Mortality and Length of Stay 
Epidemiology (Cambridge, Mass.)  2014;25(4):570-575.
Background
Clostridium difficile is a health care–associated infection of increasing importance. The purpose of this study was to estimate the time until death from any cause and time until release among patients with C. difficile, comparing the burden of those in the intensive care unit (ICU) with those in the general hospital population.
Methods
A parametric mixture model was used to estimate event times, as well as the case-fatality ratio in ICU and non-ICU patients within a cohort of 609 adult incident cases of C. difficile in the Southeastern United States between 1 July 2009 and 31 December 2010.
Results
ICU patients had twice the median time to death (relative time = 1.97 [95% confidence interval (CI) = 0.96–4.01]) and nearly twice the median time to release (1.88 [1.40–2.51]) compared with non-ICU patients. ICU patients also experienced 3.4 times the odds of mortality (95% CI = 1.8–6.2). Cause-specific competing risks analysis underestimated the relative survival time until death (0.65 [0.36–1.17]) compared with the mixture model.
Conclusions
Patients with C. difficile in the ICU experienced higher mortality and longer lengths of stay within the hospital. ICU patients with C. difficile infection represent a population in need of particular attention, both to prevent adverse patient outcomes and to minimize transmission of C. difficile to other hospitalized patients.
doi:10.1097/EDE.0000000000000119
PMCID: PMC4224274  PMID: 24815305
25.  High Level Human Herpesvirus-6 Viremia Associated with onset of Stevens-Johnson Syndrome: Report of 2 Cases 
The pathogenesis of Stevens Johnson Syndrome (SJS) remains obscure but it has been associated with various infectious agents, including members of the Herpes virus family. We present the first report of high level human herpesvirus-6 (HHV-6) viremia at the onset of SJS suggesting a possible new association. This finding supports the need for further investigation into the possible relationship between HHV-6 and SJS which may illuminate the pathogenesis of SJS and bring us closer to achieving enhanced prevention and treatment of this rare disease.
doi:10.1097/BCR.0b013e3181d0f48b
PMCID: PMC4396637  PMID: 20182379
Human Herpesvirus-6; HHV-6; Stevens-Johnson Syndrome; Herpes Viruses

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